To elucidate the pathogenesis of Parkinson' s disease and to develop a new therapy for the disease

阐明帕金森病的发病机制并开发治疗该病的新疗法

• 批准号: 20023028
• 负责人: HATTORI Nobutaka
• 金额: $ 24.96万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-20023028/
• 关键词: Parkin; PINK1; CCCP; ミトコンドリア; Mitophagy; 品質管理; オートファジー; 蛋白分解系; 遺伝性パーキンソン病; 学習能力; DJ-1; 共通機構

Parkin and PINK1 has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential-dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. In addition, we analyzed the secretion system of insulin using beta-cells originated from parkin KO mice. We identified selective impairments of phase I of insulin secretion system. This finding could be available for elucidating the pathogenesis of neuronal cell death. Moreover, we analyzed the alteration of cellular localization of both wild and mutant types of ATP13A2 that is a causative gene for Park9. The wild type localized on the outer membrane of lysosome. In contrast, the mutants located in the endoplasmic reticulum. The difference of localization could induce the loss-of-function effects.

Parkin和PINK1已经揭示了泛素化和线粒体完整性是疾病发病机制中的关键因素。在这项研究中，我们表明，PINK1是快速和组成性降解的稳态条件下，在线粒体膜电位依赖性的方式和线粒体膜电位的损失稳定PINK1线粒体积累。此外，PINK1将帕金从细胞质招募到具有低膜电位的线粒体，以启动受损线粒体的自噬降解。此外，我们使用源自parkin KO小鼠的β细胞分析了胰岛素的分泌系统。我们确定了胰岛素分泌系统I相的选择性损害。这一发现可能有助于阐明神经细胞死亡的发病机制。此外，我们分析了突变型和野生型ATP 13A2的细胞定位的改变，ATP 13A2是Park9的致病基因。野生型定位于溶酶体外膜。相反，突变体位于内质网。定位的差异可导致功能丧失效应。

项目成果

いきなり名医!パーキンソン病Q&A.

突然成为帕金森病问答的好医生！

• 发表时间: 2009
• 作者: Funayama M;et.al.;道川 誠;Hattori N;道川誠;道川誠;服部信孝;服部信孝
• 通讯作者: 服部信孝

Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease

• DOI: 10.1038/ng.485
• 发表时间: 2009-12-01
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Satake, Wataru;Nakabayashi, Yuko;Toda, Tatsushi
• 通讯作者: Toda, Tatsushi

Programmed cell death-2 isoform1 is ubiquitinated by parkin and increased in the substantia nigra of patients with autosomal recessive Parkinson's disease

• DOI: 10.1016/j.febslet.2008.12.055
• 发表时间: 2009-02-04
• 期刊: FEBS LETTERS
• 影响因子: 3.5
• 作者: Fukae, Jiro;Sato, Shigeto;Hattori, Nobutaka
• 通讯作者: Hattori, Nobutaka

Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease. 2008 Jun ; 65(6) : 802-8

391例帕金森病患者PINK1基因突变分析

• 发表时间: 2008
• 期刊: Arch Neurol 65
• 作者: Kumazawa R;et.al.
• 通讯作者: et.al.

Plenary Session III "Young onset PD"

第三次全体会议“年轻发病的帕金森病”

• 发表时间: 2009
• 作者: Funayama M;et.al.;道川 誠;Hattori N
• 通讯作者: Hattori N